The primary route of variola virus in infection in humans is via the lungs, yet remarkably little is known about orthopoxvirus-lung interactions. The focus of this project is to determine the nature of pulmonary immunopathology induced by cowpox virus, a rodent orthopoxvirus, in strains of mice that exhibit various levels of susceptibility to this virus. This system will be used as a model of orthopoxvirus-lung infections. In this study, we will characterize the sites and kinetics of viral replication in the lungs; the types of host responses to infection; and the significance of viral immunomodulatory accessory proteins for viral replication and viral pathogenesis in the lungs. Specifically this project will: Aim 1. Define the interaction of cowpox virus with resident lung cells including epithelial cells, alveolar macrophages (AM) and dendritic cells (DCs) in vitro.. Aim 2. Determine the cellular and cytokine response elicited to pulmonary cowpox in resistant and susceptible strains of mice in vivo. Aim 3. Determine the roles of cowpox virus proteins in viral replication, host immune responses, and pulmonary immunopathology in the mouse. Our determination of the host responses to virus infection will indicate which responses are important for effective protection against viral infection, and which responses may contribute to the pathogenesis. We hypothesize that whilst most host responses are likely to be beneficial to the host, abnormal types of response, such as inappropriate Th1/Th2 responses or unusual cytokine responses may be major factors in poxvirus-induced disease. Therefore, this study will be valuable in several important health-related areas including: the identification of molecular mechanisms of orthopoxvirus pathogenesis; the development of therapeutics targeting either viral proteins or host responses contributing to symptoms of disease; and the identification of ways to both attenuate vaccinia virus vaccines and increase the immunogenicity of these vaccines.